mRECIST Response Research Articles

Large, multifocal or portal vein-invading hepatocellular carcinoma (HCC) downstaged by Y90 using personalized dosimetry: safety, pathological results and outcomes after surgery.

Transarterial radioembolization (TARE) has recently been recognized as a bridging/downstaging therapy to surgery for early hepatocellular carcinomas (HCCs) with high rates of complete pathological necrosis (CPN) on liver explants. In patients with portal vein tumoral thrombus (PVTT), multifocal or large tumors, TARE has mainly a palliative role and surgery remains controversial in this poor-prognosis population. Personalized dosimetry recently proved to outperform standard dosimetry used in prior negative Y90 randomized-controlled trials. In this retrospective study, we evaluated safety, radiological and pathological response and outcomes in HCC patients with PVTT, multifocal or large tumors, who underwent surgery after downstaging using TARE with Y90-loaded glass microspheres with personalized dosimetry. Between December 2015 and October 2021, 18 unresectable patients (14/18 with PVTT) had surgery (16 resections, 2 liver transplantations) 6.2 months (range, 2-14.6 months) after a single Y90 treatment. No 90-day mortality was reported. Objective modified response criteria in solid tumors (mRECIST) response were noted in all but one patient. Complete and extensive (50-99%) necrosis was observed in 36% and 45% of tumors, respectively. The post-treatment tumor-absorbed dose significantly differed depending on the extent of pathological necrosis (P=0.045). Median overall survival and progression-free survival (PFS) were respectively of 61.8 months [95% CI: 31.4 months-not reached (NR)] and 49.3 months (95% CI: 14 months-NR). PFS was longer in patients with complete imaging response [median NR (none recurred or died) vs. 21.5 months (95% CI: 10.1 months-NR), P<0.001] and in those with complete pathological response [median NR vs. 22.5 months (95% CI: 10.1 months-NR), P<0.001]. Y90 TARE using personalized dosimetry can provide high rates of imaging and pathological response in patients with PVTT, large or multifocal HCC. Subsequent surgery is safe and leads to outcomes far exceeding expectations in an otherwise poor prognosis population with no chance for cure. Clinical trial number: NCT05045573.

Can Post-Treatment Dosimetry Predict Clinical Outcomes in Segmental Transarterial Radioembolization of Hepatocellular Carcinoma?

<h3>Purpose/Objective(s)</h3> Prognosis for patients with hepatocellular carcinoma (HCC) is poor but segmental transarterial radioembolization (STARE) using Yttrium-90 (Y90) can achieve high rates of objective response (OR) in early-stage disease. Advances in 3D computational treatment planning systems (TPS) and nuclear imaging platforms allow for accurate calculation of Y90 activity distribution after STARE. However, post-STARE dosimetry is not used to guide current clinical practice. In this single center, retrospective study of Y90 STARE, we hypothesized that 3D post-treatment dosimetry derived from bremsstrahlung single photon emission computed tomography (SPECT/CT) correlates with meaningful clinical outcomes. <h3>Materials/Methods</h3> We reviewed 24 consecutive STARE of 23 HCC patients treated with glass microspheres from 2019 to 2021. Baseline characteristics and outcomes were collected by chart and imaging review. Commercial software was used to contour gross tumor volume (GTV) and liver on post-Y90 SPECT/CT aided by deformable fusion with prior diagnostic scans. Dose distribution was assessed using the Local Deposition Model based on SPECT/CT activity maps. Mean, minimum, and maximum GTV dose, volume of GTV receiving <100 Gy, < 70 Gy and < 50 Gy, minimum isodose encompassing the hottest 2% of the GTV (D2), D5, D30, D50, D70, D95, D98, and doses to nontumorous liver were captured. Kaplan-Meier (KM) survival, multivariate regression, and areas under the receiver operating characteristic curve (AUC) were estimated using STATA. <h3>Results</h3> Most patients were Child-Pugh A (19/23) and Barcelona Clinic Liver Cancer Stage B (14/23) at baseline. Median follow up time was 12 mo (range 1-24), median prescription 185 Gy (range 120-450), and median time to best mRECIST response was 5 mo (range 1 to 12). 92% of treatments (22/24) achieved OR and 62.5% (15/24) achieved complete response (CR). Solitary lesions with long axis < 4 cm were most likely to achieve CR. CR correlated with PFS (p=0.05, median PFS for non-CR 4 months, for CR not reached) and trended to significance in OS (p=0.10, median OS for non-CR 10 mo, for CR not reached). Mean GTV dose correlated with CR only on univariate analysis while GTV volume receiving <100 Gy was highly predictive of CR (AUC 0.92) with inflection point at 3 cc. Grade 2 and 3 toxicity rates were 16.6% and 8.3% with baseline bilirubin and albumin predictive of G2+ (AUC 0.84). <h3>Conclusion</h3> In this cohort of patients with HCC treated with STARE Y90, CR correlated with meaningful clinical outcomes (PFS and OS) and a high OR rate. Our findings suggest that (1) less than CR can be identified immediately using same-day post-treatment dosimetry with suboptimal target coverage at threshold volumes most predictive and (2) concordance between suboptimal dosimetry and early post-treatment diagnostic imaging can guide recommendations for additional liver-directed therapy, with intent to convert patients to CR and improve PFS and OS. This paradigm will be tested prospectively at our institution.

Radiomics Analysis on Gadoxetate Disodium-Enhanced MRI Predicts Response to Transarterial Embolization in Patients with HCC.

Objectives: To explore the potential of radiomics on gadoxetate disodium-enhanced MRI for predicting hepatocellular carcinoma (HCC) response after transarterial embolization (TAE). Methods: This retrospective study included cirrhotic patients treated with TAE for unifocal HCC naïve to treatments. Each patient underwent gadoxetate disodium-enhanced MRI. Radiomics analysis was performed by segmenting the lesions on portal venous (PVP), 3-min transitional, and 20-min hepatobiliary (HBP) phases. Clinical data, laboratory variables, and qualitative features based on LI-RADSv2018 were assessed. Reference standard was based on mRECIST response criteria. Two different radiomics models were constructed, a statistical model based on logistic regression with elastic net penalty (model 1) and a computational model based on a hybrid descriptive-inferential feature extraction method (model 2). Areas under the ROC curves (AUC) were calculated. Results: The final population included 51 patients with HCC (median size 20 mm). Complete and objective responses were obtained in 14 (27.4%) and 29 (56.9%) patients, respectively. Model 1 showed the highest performance on PVP for predicting objective response with an AUC of 0.733, sensitivity of 100%, and specificity of 40.0% in the test set. Model 2 demonstrated similar performances on PVP and HBP for predicting objective response, with an AUC of 0.791, sensitivity of 71.3%, specificity of 61.7% on PVP, and AUC of 0.790, sensitivity of 58.8%, and specificity of 90.1% on HBP. Conclusions: Radiomics models based on gadoxetate disodium-enhanced MRI can achieve good performance for predicting response of HCCs treated with TAE.

Safety and dose-escalation study of a targeted oncolytic adenovirus, suratadenoturev (OBP-301), in patients with refractory advanced liver cancer: Phase I clinical trial.

459 Background: Suratadenoturev (OBP-301) is an oncolytic adenovirus that harbors a promoter of human telomerase reverse transcriptase ( hTERT) and is genetically modified to selectively replicate within and then lyse cancer cells. The aim of this study was to assess the safety and optimal dosage for intratumoral (IT) injection of OBP-301 in patients with advanced hepatocellular carcinoma (HCC). Methods: An open-label, non-comparative, phase I dose-escalation trial was performed in 20 patients who had refractory advanced HCC. OBP-301 was administered to the primary tumor using ultrasound guidance. A single IT injection of 1010 virus particles (VP) was administered to patients in the initial cohort (Cohort-1), and the subsequent single-dose cohorts received 1011 VP (Cohort-2), 1012 VP (Cohort-3), and 3×1012 VP (Cohort-4). A multiple dose cohort (Cohort-5) received 2×1012 VP × 3 times every 2 weeks. Each of the single-dose cohorts had 3 patients and there was a single escalating dose of OBP-301 from 1010 to 3×1012 VP. The multiple-dose cohort had 8 patients, and 6 of them received multiple escalating doses of 2×1012 VP ×3 times every 2 weeks. Results: There were 18 males and 2 females, and the median age was 59.39 years (range: 48.4–65.9). Patients had good tolerance of the single dose and multiple-dose regimens, and the maximum tolerated dose (MTD) was more than 6×1012 VP/patient. There was no evidence of toxicity with increasing dose, but there was a greater frequency of treatment-emergent adverse events (TEAEs) in Cohorts 4–5 than in Cohorts 1–3. The most common TEAEs related to OBP-301 were influenza-like illness (30%), pyrexia (15%), and fatigue, decreased platelet count, abdominal distension, and anemia (10% each). The overall intrahepatic mRECIST response occurred in 7 patients (39%) with confirmed stable disease (SD) and 11 (61%) with progressive disease (PD). The best target response occurred in 14 patients (78%) and 4 (22%) of them had PD. There was evidence of OBP-301 replication-dependent dissemination in the blood. Cohorts 4–5 had about 50% greater levels of CD8+ T cells in peripheral blood after OBP-301 injection. Conclusions: Multiple IT injections of OBP-301 are well-tolerated in advanced HCC. Although antitumor activity of the study medication alone would not be demonstrated obviously, SD observed as best local response was higher than as overall response. Improved anti-tumor efficacy can be achieved with adjusting viral injection volume to the target sites as well as with adopting the combination therapy with another immunothrapeutics in further study (JRCT ID: jRCT2033200223). Clinical trial information: NCT02293850.

Post -TACE Hepatocellular Carcinoma Response Assessment by Modified RECIST and Short Term Post TACE Survival

Background: Transarterial Chemoembolization(TACE) although not curative, can improve the overall survival of patients. Modified response evaluation criteria in solid tumors (mRECIST) is used for the evaluation of the treatment response in patients after TACE. Aims: To assess the post-TACE hepatocellular carcinoma(HCC) response by mRECIST criteria and the short term post-TACE survival. Methods: All patients underwent super selective TACE using epirubicin and mRECIST response was calculated using MRI. Factors were analyzed for the post-TACE response and survival. Results: Among 54 patients with HCC, 42 were analyzed. The mean age was 59.12 ± 8.74 years. Predominant etiology was NASH (31%) and alcohol (23.8%). 23 patients had complete response(CR), 8 patients had partial response(PR), 4 patients had stable disease(SD) and7 patients had progressive disease(PD) as per mRECIST criteria. Objective response(OR) is defined as patients achieving either CR or PR and poor response(PoR) as patients achieving either SD or PD. 73.8 % had an objective response and 26.2% had a poor response. HAP score(P=0.003) and CHILD stage(P=0.011) were the most important predictors of a favorable mRECIST response. 72.7% died during the study period. There was a significant survival difference among patients with (OR) (25.64 months) than patients with (PR) (13.10 months), P=0. 001. mRECIST response predicted survival among the patients but it was not an independent factor as per multivariate analysis (HR=1.08, P=0.02). The independent predictors for survival were post-TACE decompensation (B-1.43, P=0.03), ECOG performance status (B-1.41, P=0.010), and the number of malignant lesions for TACE (HR 2.20, P=0.017). Conclusion: Patients undergoing TACE for intermediate stage HCC has a significant survival advantage when they achieve an objective response as per mRECIST. Proper selection of patients for TACE is important for getting an objective response and for better short-term survival.

Utility of Early Posttreatment PET/CT Evaluation Using FDG or 18F-FCH to Predict Response to 90Y Radioembolization in Patients With Hepatocellular Carcinoma.

BACKGROUND. Assessment of hepatocellular carcinoma (HCC) treatment response after transarterial radioembolization (TARE) is challenging, because response by conventional imaging criteria may not become apparent until 6 months after treatment. Though HCC exhibits variable avidity for FDG, some cases of HCC without avidity for FDG show avidity for 18F-fluorocholine (18F-FCH). OBJECTIVE. The purpose of this study was to evaluate the utility of early posttreatment evaluation by PET/CT using FDG or 18F-FCH to predict 6-month treatment response and survival after TARE in patients with HCC. METHODS. This retrospective study included 37 patients (mean age, 67 years; 34 men, three women) with documented HCC treated by TARE who underwent both pre-treatment FDG PET/CT and 18F-FCH PET/CT and early FDG PET/CT and/or 18F-FCH PET/CT 4-8 weeks after treatment; FDG PET/CT and 18F-FCH PET/CT examinations were performed on separate dates. Only one of 73 initially identified potentially eligible patients was excluded because of lack of HCC avidity for both FDG and 18F-FCH. Response assessment by modified RECIST (mRECIST) on multiphase CT or MRI was performed at 1 month and 6 months in 23 patients. Early responses seen on PET/CT and 1-month mRECIST response were assessed as predictors of 6-month mRECIST response. Univariable and multivariable predictors of overall survival (OS) were identified. RESULTS. On pretreatment PET/CT, 28 (76%) patients were FDG-positive (showed visual uptake on FDG PET/CT and tumor-to-normal liver ratio > 1.15), 15 (41%) were FCH-positive (showed visual uptake on 18F-FCH PET/CT), and six (16%) were both FDG-positive and FCH-positive. Twelve of 28 FDG-positive HCCs exhibited early response by FDG PET/CT; seven of 15 FCH-positive HCCs exhibited early response by 18F-FCH PET/CT. Twelve (52%) patients exhibited 6-month mRECIST response. Response seen on early posttreatment PET/CT exhibited 100% (12/12) sensitivity and 100% (11/11) specificity for 6-month mRECIST response, whereas 1-month mRECIST response exhibited 67% (8/12) sensitivity and 100% (11/11) specificity for 6-month mRECIST response. Response seen on early posttreatment PET/CT was a significant independent predictor of OS on univariable (hazard ratio [HR], 0.4; 95% CI, 0.2-0.9; p = .03) and multivariable (HR, 0.2; 95% CI, 0.1-0.8; p = .01) analyses. CONCLUSION. Early evaluation after TARE by PET/CT using FDG or 18F-FCH may pre dict 6-month response and OS in patients with HCC. CLINICAL IMPACT. Early posttreatment evaluation with PET/CT could help more reliably identify true nonresponders after TARE, which in turn could prompt early response-adapted therapeutic management.

Long Term Efficacy and Assessment of Tumor Response of Transarterial Chemoembolization in Neuroendocrine Liver Metastases: A 15-Year Monocentric Experience.

Simple SummaryNeuroendocrine tumors (NET) are rare tumors, with long-term survival even for patients with liver metastases. Transarterial chemoembolization (TACE) is one of the most widely used treatments in this setting. The aim of the study was to assess the long-term efficacy of TACE in a large cohort of patients with NET liver metastases and to correlate imaging findings with survival. In our study including 202 patients with NET liver metastases and a mean follow-up of 8.2 years, TACE was effective to provide disease control for 26 months and a 5.3-year median overall survival (OS). Imaging responses using RECIST and mRECIST criteria were significantly correlated to OS: the median-OS was twice as long among mRECIST responders versus non-responders, with 80.5 months and 39.6 months respectively. These findings are of major importance for everyday practice as they confirm TACE’s effectiveness and usefulness of imaging evaluation to better tailor patient treatment and repeat TACE sessions whenever necessary.Background: transarterial chemoembolization (TACE) is an established treatment for neuroendocrine tumor (NET) liver metastases. The aim was to evaluate the long-term treatment efficacy of TACE for NET liver metastases, and correlate imaging response with survival. Methods: this IRB-approved, single-center, retrospective study evaluated all TACE procedures performed for NET liver metastases from 2003–2017 for imaging tumor response (RECIST and mRECIST), time to liver progression (TTLP), time to untreatable progression with TACE (TTUP), and overall survival (OS). Patient, tumor, and treatment characteristics were analyzed as prognostic factors. Survival curves according to the Kaplan–Meier method were compared by Log-rank test. Tumor responses according to RECIST and mRECIST were correlated with OS. Results: 555 TACE procedures were performed in 202 NET patients (38% grade 1, 60% grade 2) with primary tumors originating from pancreas, small bowel, and lung (39, 26, and 22% respectively). Median follow-up was 8.2 years (90–139 months). Median TTLP and TTUP were 19.3 months (95%CI 16.3–22.3) and 26.2 months (95%CI 22.3–33.1), respectively. Median OS was 5.3 years (95%CI 4.2–6.7), and was higher among mRECIST responders (80.5 months; 95%CI 64.6–89.8) than in non-responders (39.6 months; 95%CI = 32.8–60.2; p < 0.001). In multivariable analysis, age, tumor grade and liver involvement predicted worse OS, whereas administration of somatostatin analogs correlated with improved OS. Conclusion: TACE for NET liver metastases provides objective response and sustained local disease control rates. RECIST and mRECIST responses correlate with OS.

A Single-Center 10-Year Retrospective Analysis of Cryoablation for the Management of Desmoid Tumors

PurposeTo determine the efficacy and safety of cryoablation in patients with desmoid tumors (DTs) retrospectively over a 10-year period at a single institution. Materials and MethodsBetween February 25, 2010, and February 25, 2020, 25 patients (age, 12–80 years) with 26 lesions (mean preprocedural tumor volume was 237 cm3) were treated over 44 cryoablation procedures. Eleven patients were treated with first-line therapy. Fourteen patients had previous medical therapy, radiotherapy, and/or surgery. Subsequent clinical follow-up, imaging outcomes, and safety were analyzed for technical success, change in total lesion volume (TLV) and viable tumor volume (VTV), modified response evaluation criteria in solid tumors (mRECIST), progression-free survival (PFS) for tumor progression and symptom recurrence, symptom improvement, and procedure-related complications. Symptomatic improvement was defined as documentation of relief of pain (partial or complete) and/or functional impairment. ResultsAll procedures were technically successful. At 7–12 months, median changes in TLV and VTV were −6.7% (P = .809) and −43.7% (P = .01), respectively. At 10–12 months, the mRECIST responses were complete response, 0%; partial response, 61.5% (8/13); stable disease, 30.8% (4/13); and progressive disease, 7.7% (1/13). The median PFS for tumor progression and symptom recurrence were not reached, with a median follow-up of 15.3 and 21.0 months, respectively. Symptomatic relief (partial or complete) was achieved in 96.9% (32/33) of patients. One major complication was noted (2.4%). ConclusionsIn this retrospectively identified cohort, cryoablation was effective and safe for the local control of extra-abdominal DTs in short-term follow-up.

Cost-Effectiveness of Imaging Tumor Response Criteria in Hepatocellular Cancer After Transarterial Chemoembolization.

Several tumor response criteria on cross-sectional imaging have been used in hepatocellular cancer after locoregional, intra-arterial therapy. The cost implications of their efficacy and accuracy are not well established. To evaluate cost-effectiveness of quantitative European Association for Study of the Liver (qEASL) compared with Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST) response criteria. A Markov decision-analytic model was constructed, accounting for both costs and outcomes from a payor perspective. Three different tumor imaging response criteria were evaluated: (1) qEASL, (2) RECIST, and (3) mRECIST. Input parameters were derived from the most comprehensive literature available focusing on the assessment of liver tumor response after transarterial chemoembolization. Deterministic and probabilistic sensitivity analyses were performed. Base case calculation showed qEASL to be the dominant strategy, with the highest effectiveness (1.06 quality-adjusted life years (QALY), as compared with 1.05 QALY in mRECIST and 1.02 QALY in RECIST). The expected costs of qEASL, mRECIST, and RECIST were $451,773, $460,489, and $459,004, respectively. qEASL was more cost-effective than RECIST in 71.50% of the 10,000 iterations and mRECIST in 69.26% of the iterations. One-way sensitivity analysis varying the cost showed that qEASL remained cost-effective until its additional cost was above $9,994. Our study demonstrates qEASL to be the most cost-effective tumor response assessment criterion, with substantial cost savings as compared with RECIST and mRECIST for patients with hepatocellular carcinoma after transarterial chemoembolization.

Post-treatment CT LI-RADS categories: predictors of overall survival in hepatocellular carcinoma post bland transarterial embolization.

The LI-RADS Treatment Response (LR-TR) algorithm was introduced in 2017 to assist radiologists in assessing hepatocellular carcinoma (HCC) response following locoregional therapy. The objective of this study was to evaluate the associations between pre-treatment LI-RADS diagnostic categories, post-treatment LR-TR categories, and mRECIST response categories with overall survival (OS) of patients with HCC. This retrospective study included untreated patients with one or two lesions who underwent transarterial embolization with or without concomitant ablation from December 2003 to December 2017. Two radiologists (R1 and R2) reviewed pre- and post-treatment CT imaging. Associations between pre- and post-treatment variables, including post-treatment LR-TR categories (Viable, Equivocal, Nonviable), with OS were assessed using the Kaplan-Meier method and Cox proportional hazards regression. Eighty-five patients were included (median age = 71years, range 50-87; 17 women). The median OS from first embolization was 43.92months. Pre- and post-treatment tumor size, pre-treatment LR-TIV (compared with LR-5), and post-treatment LR-TR Viable (compared with LR-TR Nonviable) were associated with OS (p < 0.05 for all). Median OS was shorter for LR-TR Viable patients (R1, 25.64months, 95% CI 18.58-35.70; R2, 26.43months 95% CI 20.68-43.92) than for LR-TR Nonviable patients (64.21months R1 and R2, 95% CI 42.71-92.45 and 36.30-94.09, respectively). mRECIST categories showed similar associations with OS. Inter-reader agreement was moderate for LI-RADS categories (κ = 0.57, 95% CI 0.35-0.78) and substantial for LR-TR categories (κ = 0.68, 95% CI 0.55-0.81). LR-TR categories show a strong association with OS in HCC patients treated with transarterial embolization.

4:12 PM Abstract No. 145 Yttrium-90 radiation segmentectomy for hepatic metastases: a multi-institutional study of safety and efficacy

Yttrium-90 (Y-90) radiation segmentectomy has shown great promise for treatment of localized primary liver cancer. This study assessed outcomes of segmental Y-90 radioembolization for hepatic metastases, not amenable to surgical resection or ablation. A retrospective review was performed on patients with hepatic metastases treated with radiation segmentectomy at two institutions over 6 years (2012-2018). 32 patients with 53 tumors (14 patients with >1 tumor) underwent segmental radioembolization, with ablative-level doses exceeding 200 Gy to perfused tissue. Patients were not candidates for surgical resection or thermal ablation due to medical comorbidities, presence of extrahepatic disease, tumor size, or tumor location. Hepatic metastases were from colorectal cancer (34%), neuroendocrine tumors (28%), sarcoma (19%), and others (19%). 62% of patients had liver-only disease, and 38% had liver-dominant disease. 75% of patients had an ECOG performance status of 0. All patients had normal liver function tests at baseline. With the exception of biologic agents, ongoing systemic chemotherapy was not discontinued. Toxicity, tumor response, tumor progression, and survival were assessed. Median tumor size was 3.6 cm (range, 1.2-6.1 cm). Toxicity rates were low, with no hepatic-related CTCAE grade 3 or 4 toxicity and a 6% rate of CTCAE grade 3 leukopenia. Target tumor objective RECIST response rate was 74% (19% complete response, 55% partial response) and disease control was 89%. For patients with hypervascular tumors (n = 22), target tumor objective mRECIST response rate was 100%, with a complete response in 86%. During a median follow-up of 12 months, overall survival was 94% and target tumor progression occurred in 25% of treated tumors. Y-90 radiation segmentectomy for hepatic metastases demonstrates high rates of tumor response with low rates of target tumor progression. Toxicities are minimal, despite many patients receiving concurrent chemotherapy. Radiation segmentectomy should be considered for patients with liver-dominant metastatic disease who are not ideal candidates for surgical resection or ablation.

Association of objective response by mRECIST with better overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC) treated with systemic therapies: A systematic review and meta-analysis of randomized controlled trials.

586 Background: EASL guidelines for management of HCC recommends assessing tumor response according to mRECIST at all stages of the disease (EASL guidelines, J Hep 2018). Several studies have reported that objective response by mRECIST predicted overall survival (OS) but definitive data are still lacking. Methods: The PubMed database and ASCO meeting library were searched for full reports of randomized trials in patients with advanced HCC treated by systemic therapy up to August 31, 2018. We search strategy used the following terms: HCC, mRECIST, OS and objective response rate (ORR). We assess the association between ORR and OS in a meta-analysis of pooled data by using random effects model comparing patients achieving objective response (complete or partial response) versus non responders (stable disease, progressive disease) and displayed the results as per hazard ratio (HR, 95% CI). Results: Among 14 articles assessing response by mRECIST to systemic therapies in randomized studies in advanced HCC, 4 studies (5 trials) including 1,463 patients were considered eligible. Systemic therapies tested included lenvatinib, sorafenib, brivanib and nintedanib. Overall, ORR as per mRECIST ranged from 11.5% to 18.8%, being the median OS for responders of 18.5 to 27.2 mo (as opposed 8.9 to 11.4 for non-responders). As per random effects model, the HR for overall survival (responders versus non responders) was 0.47 (95% confidence interval 0.34–0.66, p&lt;0.001). Conclusions: Objective response by mRECIST to systemic therapies in patients with advanced HCC is significantly and strongly associated to OS. Patients achieving an objective response can expect a significantly longer OS.

Abstract 3176: Biomarker identification using xenograft mouse model based clinical trial simulation and artificial intelligence data analytics

Abstract The growing number of anti-cancer drugs available at different stages of clinical development combined with the broadening potential use of combination therapy further complexifies the early identification of companion markers, markers of synergy as well as novel indications for existing and new drug combinations. Well characterized patient derived xenograft mouse models (PDX), combined with Artificial Intelligence tools that can integrate and analyze the broad range of generated data can help address this challenge. PDX experiments can providing an opportunity to simulate a clinical assessment using multiple mice models.In this study, we developed a PDX platform combined with the KEM® Artificial Intelligence data analytics, that is based on Formal Concept Analysis, to simulate a clinical trial and identify biomarkers of response. The platform was tested on colon cancer patient derived PDX. Respectively mRECIST response and survival of respectively 21 and 26 PDXs against Oxalipaltin combined with 5-Fluorouracil and folinic acid (Folfox) was experimentally assessed against a placebo, simulating a clinical trial-like setting with 2 arms. Biomarkers of response (mRECIST) and survival were identified using KEM®, combined with statistical modelling (Cox survival-modelling). 24 candidate biomarker genes were identified including PGAP3, ERBB2, NOTCH2, WDR70, and ZNF227. Alone or combined, these biomarkers are significantly linked to an increase or decrease of the survival PDX (p ranging from 2.2e-10 to 0.048, odd-ratio ranging from 0.12 to 10.00), with the potential to be used as inclusion or exclusion biomarkers. This work demonstrates the ability of a combined PDX / Artificial Intelligence platform to simulate clinical trials and identify biomarkers of drug efficacy and synergy, thus fostering the design of precision medicine clinical trials. Citation Format: M Afshar, Francis Bichat, Olivier Duchamp, A Etcheto, Damien France, M Kindermans, Caroline Mignard, F Parmentier, Hery Ratsima. Biomarker identification using xenograft mouse model based clinical trial simulation and artificial intelligence data analytics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3176.

Alpha-Fetoprotein, Des-Gamma-Carboxy Prothrombin, and Modified RECIST Response as Predictors of Survival after Transarterial Radioembolization for Hepatocellular Carcinoma

PurposeTo evaluate the prognostic role of alpha-fetoprotein (AFP), des-gamma-carboxy protein (DCP), and modified Response Evaluation Criteria in Solid Tumors (mRECIST) in patients with hepatocellular carcinoma after transarterial radioembolization (TARE). Materials and MethodsDuring 2009–2016, 63 patients with AFP >20 ng/mL, DCP >20 mAU/mL, and Child-Pugh class A who were treated with TARE were evaluated using landmark and risk-of-death method after TARE. Both resin microspheres (n = 46) and glass microspheres (n = 17) were used. AFP or DCP response was defined as more than 50% decrease from baseline. mRECIST response was defined as complete or partial response. Median age was 60 years, and the proportion of male sex was 77.8% (n = 49). The proportions of patients with Barcelona Clinic Liver Cancer stages A, B, and C were 7.9% (n = 5), 46.0% (n = 29), and 46.0% (n = 29), respectively. ResultsAt the 3-month landmark, AFP, DCP, and mRECIST responders lived longer than nonresponders (median overall survival, 75.8 vs 7.6 months for AFP; 75.8 vs 7.1 months for DCP; and 75.8 vs 10.0 months for mRECIST; all P < .05). The 6-month risk of death at the 3-month landmark was statistically different only between DCP responders and nonresponders (P = .002). In multivariate analysis, age less than 70 years (P = .024), absence of distant metastasis (P = .049), DCP response (P = .003), and mRECIST response (P = .003) were independent predictors for overall survival at the 3-month landmark after TARE. ConclusionsAFP, DCP, and mRECIST responders showed better prognosis than nonresponders after TARE, and DCP response was a more potent predictor than AFP response. Tumor marker response, as well as radiologic response, may be useful to predict post-TARE survival.

Prediction of Tumor Control in 90Y Radioembolization by Logit Models with PET/CT-Based Dose Metrics.

The aim of this work was to develop models for tumor control probability (TCP) in radioembolization with 90Y PET/CT-derived radiobiologic dose metrics. Methods: Patients with primary liver cancer or liver metastases who underwent radioembolization with glass microspheres were imaged with 90Y PET/CT for voxel-level dosimetry to determine lesion absorbed dose (AD) metrics, biological effective dose (BED) metrics, equivalent uniform dose, and equivalent uniform BED for 28 treatments (89 lesions). The lesion dose-shrinkage correlation was assessed on the basis of RECIST and, when available, modified RECIST (mRECIST) at first follow-up. For a subset with mRECIST, logit regression TCP models were fit via maximum likelihood to relate lesion-level binary response to the dose metrics. As an exploratory analysis, the nontumoral liver dose-toxicity relationship was also evaluated. Results: Lesion dose-shrinkage analysis showed that there were no significant differences between model parameters for primary and metastatic subgroups and that correlation coefficients were superior with mRECIST. Therefore, subsequent TCP analysis was performed for the combined group using mRECIST only. The overall lesion-level mRECIST response rate was 57%. The AD and BED metrics yielding 50% TCP were 292 and 441 Gy, respectively. All dose metrics considered for TCP modeling, including mean AD, were significantly associated with the probability of response, with high areas under the curve (0.87-0.90, P < 0.0001) and high sensitivity (>0.75) and specificity (>0.83) calculated using a threshold corresponding to 50% TCP. Because nonuniform AD deposition by microspheres cannot be determined by PET at a microscopic scale, radiosensitivity values extracted here by fitting models to clinical response data were substantially lower than reported for in vitro cell cultures or for external-beam radiotherapy clinical studies. There was no correlation between nontumoral liver AD and toxicity measures. Conclusion: Despite the heterogeneous patient cohort, logistic regression TCP models showed a strong association between various dose metrics and the probability of response. The performance of mean AD was comparable to that of radiobiologic dose metrics that involve more complex calculations. These results demonstrate the importance of considering TCP in treatment planning for radioembolization.

Comparison of α-Fetoprotein Criteria and Modified Response Evaluation Criteria in Solid Tumors for the Prediction of Overall Survival of Patients with Hepatocellular Carcinoma after Transarterial Chemoembolization

PurposeTo evaluate the value of α-fetoprotein (AFP) classification criteria in predicting tumor response and patient survival and to discuss the agreement between AFP criteria and modified Response Evaluation Criteria In Solid Tumors (mRECIST). Materials and MethodsBetween January 2011 and December 2014, 147 patients with unresectable hepatocellular carcinoma (HCC) with baseline AFP levels ≥ 400 ng/mL who underwent transarterial chemoembolization as initial treatment were retrospectively enrolled for AFP/imaging correlation analysis. AFP-based response was classified as complete response (CR) in cases of AFP level normalization, partial response (PR) in cases of > 50% decrease vs baseline, stable disease (SD) in cases of −50% to +30% change vs baseline, or progressive disease (PD) in cases of > 30% increase vs baseline. Intermethod agreement between the 2 methods was assessed by Cohen κ coefficient. Response rates according to AFP and mRECIST were compared, and the association between response rate and overall survival (OS) was evaluated. ResultsThe κ value for agreement between AFP criteria and mRECIST was 0.549 (ie, moderate), with objective response and disease control rates of 36.1% and 63.3% per AFP criteria and 34.7% and 46.3% per RECIST (P = .807 and P = .003), respectively. Although AFP criteria and mRECIST showed significantly prognostic strata for CR, PR, SD, and PD after chemoembolization (P < .001 for both), some overlap in radiologic PD survival curves was observed. The OS of AFP-based disease control (ie, CR/PR/SD) was significantly longer than that of AFP-based PD among patients with radiologic PD (9.0 vs 6.0 mo; P < .001). ConclusionsThe defined AFP response moderately correlated with mRECIST response and yielded accurate prognostic prediction in patients with HCC and AFP levels ≥ 400 ng/mL treated with chemoembolization.

Hepatocellular Carcinoma Tumor Dose Response After 90Y-radioembolization With Glass Microspheres Using 90Y-SPECT/CT-Based Voxel Dosimetry

To investigate hepatocellular carcinoma tumor dose-response characteristics based on voxel-level absorbed doses (D) and biological effective doses (BED) using quantitative 90Y-single-photon emission computed tomography (SPECT)/computed tomography (CT) after 90Y-radioembilization with glass microspheres. We also investigated the relationship between normal liver D and toxicities. 90Y-radioembolization activity distributions for 34 patients were based on quantitative 90Y-bremsstrahlung SPECT/CT. D maps were generated using a local-deposition algorithm. Contrast-enhanced CT or magnetic resonance imaging scans of the liver were registered to 90Y-SPECT/CT, and all tumors larger than 2.5 cm diameter (53 tumors) were segmented. Tumor mean D and BED (Dmean and BEDmean) and dose volume coverage from 0% to 100% in 10% steps (D0-D100 and BED0-BED100) were extracted. Tumor response was evaluated on follow-up using World Health Organization (WHO), Response Evaluation Criteria in Solid Tumors (RECIST), and modified RECIST (mRECIST) criteria. Differences in dose metrics for responders and nonresponders were assessed using the Mann-Whitney U test. A univariate logistic regression model was used to determine tumor dose metrics that correlated with tumor response. Correlations among tumor size, tumor Dmean, and tumor dose heterogeneity (defined as the coefficient of variation) were assessed. The objective response rates were 14 of 53, 15 of 53, and 30 of 53 for WHO, RECIST, and mRECIST criteria, respectively. WHO and RECIST response statuses did not correlate with D or BED. For mRECIST responders and nonresponders, D and BED were significantly different for Dmean, D20 to D80, BEDmean, and BED0 to BED80. Threshold doses (and the 95% confidence interval) for 50% probability of mRECIST response (D50%) were 160 Gy (123-196 Gy) for Dmean and 214 Gy (146-280 Gy) for BEDmean. Tumor dose heterogeneity significantly correlated with tumor volume. No statistically significant association between Dmean to normal liver and complications related to bilirubin, albumin, or ascites was observed. Hepatocellular carcinoma tumor dose-response curves after 90Y-radioembolization with glass microspheres showed Dmean of 160 Gy and BEDmean of 214 Gy for D50% with a positive predictive value of ∼70% and a negative predictive value of ∼62%. No complications were observed in our patient cohort for normal liver Dmean less than 44 Gy.

Angiosomal radiopathologic analysis of transarterial radioembolizationfor the treatment of hepatocellular carcinoma.

To assess the radiopathologic correlation following Yttrium-90 transarterial radioembolization (TARE) of hepatocellular carcinoma (HCC) using variable radiodosimetry to identify imaging surrogates of histologic response. Twelve patients with HCC underwent ablative (≥190Gy) and/or non-ablative (<190Gy) TARE delivered in a segmental, lobar, or combined fashion as a surgical neoadjuvant or bridge to transplantation. Both targeted tumor and treatment angiosome were analyzed before and after TARE utilizing hepatocyte-specific contrast-enhanced MRI or contrast-enhanced CT. Responses were graded using EASL and mRECIST criteria. Histologic findings including percent tumor necrosis and adjacent hepatic substrate effects were correlated with imaging features. Complete pathologic necrosis (CPN) was observed in 7/12 tumors post-TARE. Ablative and non-ablative dosing resulted in CPN in 5/6 and 2/6 tumors, respectively. Hyperintensity on T2-weighted imaging, the absence of hepatocyte-specific gadolinium contrast uptake, and plateau or persistent enhancement kinetics in the angiosome correlated with CPN and performed similarly to EASL and mRECIST criteria in predicting CPN. The absence of hepatocyte-specific contrast uptake, increased signal on T2-weighted sequences, and plateau or persistent enhancement in the angiosome may represent MRI surrogates of CPN following TARE of HCC. These findings correlated with EASL and mRECIST response criteria. Further investigation is needed to determine the role of these findings as possible adjuncts to conventional imaging criteria.

Changes of alpha-fetoprotein levels could predict recurrent hepatocellular carcinoma survival after trans-arterial chemoembolization.

BackgroundThere is paucity of information concerning whether AFP change is a predictor of prognosis for recurrent hepatocellular carcinoma (RHCC) patients after trans-arterial chemoembolization (TACE).MethodsA total of 177 RHCC patients who received TACE as first-line therapy were retrospectively analyzed. The patients were classified into three groups according to their pre-TACE and post-TACE AFP levels (group A: AFP decreased, group B: AFP consistent normal, and group C: AFP increased). The recurrence to death survival (RTDS) and overall survival (OS) were estimated by the Kaplan-Meier method, and compared by the log-rank test. Multivariate analyses were performed to identify prognostic factors for OS and RTDS.ResultsThere was no significant difference among the three groups concerning the baseline characteristics. The median overall survival (OS) was 74.5 months in group A (95% confidence interval (CI): 63.5, 85.6), 64.0 months in group B (95% CI: 52.3, 75.7) and 29.0 months in group C (95% CI: 24.1, 33.9; P<0.001). The median recurrence to death survival (RTDS) was 66.5 months (95% CI: 53.4, 79.6) in group A, 50.4 months (95% CI: 39.5, 61.4) in group B and 17.7 months (95% CI: 13.4, 22.1; P<0.001) in group C. Multivariate analysis revealed that tumor size at resection stage, tumor number at recurrent stage, cycles of TACE, mRECIST response and AFP change after TACE were significant independent risk factors for RTDS and OS.ConclusionsAFP change could predict the prognoses of patients with RHCC who received trans-arterial chemoembolization, which may help clinicians make subsequent treatment decision.

Tumor response assessment by MRI following stereotactic body radiation therapy for hepatocellular carcinoma.

BackgroundTo evaluate the MRI features of a tumor response, local control, and predictive factors of local control after stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC).MethodsThirty-five consecutive patients with 48 HCCs who were treated by SBRT were included in this retrospective study. All patients provided written informed consent to be treated by SBRT, and prior to inclusion they authorized use of the treatment data for further studies. The assessment was made using MRI, with determination of local and hepatic responses according to Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST) criteria during a two-year follow-up.ResultsThe local response rate according to mRECIST was higher than with RECIST. A tumor diameter less than 20 mm at baseline was an independent predictive factor for RECIST and mRECIST responses, as was diffusion-weighted signal for RECIST. During follow-up, a tumor diameter of <20 mm (p = 0.034) and absence of a high intensity on T2-weighted (p = 0.006) and diffusion-weighted images (p = 0.039) were associated with a better response according to RECIST. Post-treatment changes include peritumoral ring-like enhanced changes with high intensity on T2-weighted images.ConclusionsSBRT is a promising technique for the treatment of inoperable HCC. Post-treatment changes on MRI images can resemble tumor progression and as such must be adequately distinguished. The regression of tumorous enhancement is variable over time, although diffusion-weighted and T2-weighted intensities are predictive factors for tumor RECIST responses on subsequent MRIs. They hence provide a way to reliably predict treatment responses.